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Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease
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Number of Authors: 282019 (English)In: Nature Communications, E-ISSN 2041-1723, Vol. 10, article id 2110Article in journal (Refereed) Published
Abstract [en]

Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ER alpha) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.

Place, publisher, year, edition, pages
2019. Vol. 10, article id 2110
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-169248DOI: 10.1038/s41467-019-10100-8ISI: 000467371400008PubMedID: 31068593OAI: oai:DiVA.org:su-169248DiVA, id: diva2:1323736
Available from: 2019-06-12 Created: 2019-06-12 Last updated: 2023-03-28Bibliographically approved
In thesis
1. RNA Polymerase I regulation by chromatin remodelling
Open this publication in new window or tab >>RNA Polymerase I regulation by chromatin remodelling
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cell proliferation and growth is correlated with effective protein synthesis and ribosome biogenesis. The transcription of the 47S pre-ribosomal RNA by RNA Polymerase I (RNA Pol I) machinery is the rate-limiting step of ribosome biogenesis and can accounts for more than 50% of total cellular transcription. RNA Polymerase I transcription is a highly energy-consuming process which requires regulation at various stages.

In the work presented in this thesis, we have investigated the regulation of RNA Pol I transcription, and investigated the stress response triggered by impaired RNA Pol I transcription. We showed in study I that the ATP dependent chromatin remodelling complex B-WICH is required to maintain an open chromatin landscape at the ribosomal DNA (rDNA) gene promoter in order to allow for transcription initiation by RNA Pol I. In absence of B-WICH, the NuRD complex reconfigures the chromatin landscape to an inaccessible state. We showed in study II that impairment of RNA Pol I transcription by deleting WSTF, a core subunit of B-WICH resulted in cell cycle arrest and apoptosis. More severe inhibition of RNA Pol I transcription through chemical compounds resulted in activation of cellular stress response cascades including but not limited to cell cycle arrest, unfolded protein response and oxidative stress response. We showed in study III that RNA Pol I transcription was increased during epithelial-mesenchymal transition (EMT) in the context of development and disease. The association of the EMT-driving transcription factor SNAIL1 with the rDNA gene promoter was shown to be essential in EMT triggered RNA Pol I transcription. The work presented in this thesis demonstrates the importance of RNA Pol I transcription regulation in maintaining cellular homeostasis.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2020. p. 55
Keywords
RNA Pol I, ribosome genes, chromatin remodelling, WSTF, CHD4
National Category
Cell Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-184045 (URN)978-91-7911-210-3 (ISBN)978-91-7911-211-0 (ISBN)
Public defence
2020-09-25, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, Stockholm, 09:00 (English)
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Supervisors
Available from: 2020-09-02 Created: 2020-08-12 Last updated: 2022-02-26Bibliographically approved

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Petersen, JulianGuo, YuanÖstlund Farrants, Ann-Kristin

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